Lack of potentiation of bradykinin by angiotensin-(1-7) in a type 2 diabetes model: Role of insulin Viviani Milan Ferreira Rastelli, Maria Aparecida Oliveira, Rosangela dos Santos, Rita de Ca ´ ssia Tostes Passaglia, Dorothy Nigro, Maria Helena Catelli de Carvalho, Zuleica Bruno Fortes * Department of Pharmacology, Institute of Biomedical Science, University of Sa ˜ o Paulo. Av. Prof. Lineu Prestes, 1524, Cidade Universita ´ ria, 05508-900 Sa ˜ o Paulo, Brazil 1. Introduction The Renin–Angiotensin System (RAS) and the Kallikrein- Kinin System (KKS) each encompasses a large number of molecules with several participating in both systems. The RAS generates a family of bioactive angiotensin peptides among them Angitensin-(1-7) (Ang-(1-7)) is gaining impor- tance in the last years. The KKS also generates a family of bioactive peptides, bradykinin (BK) being one of the most important [8]. In diabetes mellitus, several changes affect the KKS. It has been demonstrated that BK can induce glucose transporter GLUT4 translocation with increase in insulin sensitivity and reduction of plasma glucose and free fatty acids [9]. Therefore, the reduced response to BK observed in the disease [13–16,25] might contribute to its pathogenesis. peptides 28 (2007) 1040–1049 article info Article history: Received 4 October 2006 Received in revised form 5 February 2007 Accepted 5 February 2007 Published on line 14 February 2007 Keywords: Type 2 diabets Bradykinn Angiotensin-(1-7)-insulin abstract Considering the growing importance of the interaction between components of kallikrein- kinin and renin–angiotensin systems in physiological and pathological processes, particu- larly in diabetes mellitus, the aim of the present study was to investigate the interaction between angiotensin-(1-7) (Ang-(1-7)) and bradykinin (BK), important components of these systems in an insulin resistance model of diabetes, and the effect of insulin on it. For this the response of mesenteric arterioles of anesthetized neonatal streptozotocin-induced (n-STZ) diabetic and control rats was evaluated using intravital microscopy. Though capable of potentiating BK in non-diabetic rats, Ang-(1-7) did not potentiate BK in n-STZ rats. Chronic but not acute insulin treatment restored the potentiation. This restorative effect of insulin was abolished by a K+ channel blocker (tetraethylammonium), by nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester) and by a cyclooxygenase inhibitor (indometha- cin). On the other hand, Na + -,K + -ATPase inhibition (by ouabain) did not abolish the effect of insulin. There was no difference in mRNA and protein expression of B1 and B2 kinin receptor subtypes between n-STZ diabetic and control rats. Insulin treatment did not alter the kinin receptor expression. Our data allow us to conclude that diabetes impaired the interaction between BK and Ang-(1-7) and that insulin restores it. The restoring effect of insulin depends on membrane hyperpolarization, nitric oxide release and cyclooxygenease metabolites but not Na+K+-ATPase. Alteration of kinin receptor expression might not be involved in the restoring effect of insulin on the potentiation of BK by Ang-(1-7). # 2007 Elsevier Inc. All rights reserved. * Corresponding author. Tel.: +55 11 30917317; fax: +55 11 30917317. E-mail address: zbfortes@icb.usp.br (Z.B. Fortes). available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/peptides 0196-9781/$ – see front matter # 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2007.02.006